Dolutegravir (I) is chemically known as (4R,12aS)—N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide.
Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Dolutegravir is being marketed under the trade name Tivicay®.
U.S. Pat. No. 8,129,385 disclosed Dolutegravir or its pharmaceutically acceptable salts thereof.
US '385 also discloses a process for the preparation of Dolutegravir (I). The process involves the condensation of 5-benzyloxy-4-hydroxy-6-hydroxymethyl nicotinic acid (III) with 2,4-difluorobenzylamine (IV) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-4-hydroxy-6-hydroxymethyl nicotinic acid amide (V), which is further under goes oxidation using manganese dioxide (MnO2) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-6-formyl-4-hydroxy-nicotinic acid amide (VI). This amide compound (VI) is reacted with sodium chlorite (NaClO2) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid (VII), which is further treated with methanol (MeOH) to produce 3-benzyloxy-5-(2,4-difluorobenzyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester (VIII). The methyl ester compound (VIII) is reacted with 3-bromopropene to produce 1-allyl-3-benzyloxy-5-(2,4-difluorobenzyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (IX), which is further reacted with potassium osmate dihydrate (K2OsO4.2H2O) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4-dihydropyridine-2-carboxylic acid methyl ester (X). The compound (X) is reacted with (R)-3-amino-1-butanol (II) to produce benzyloxy Dolutegravir (XI), which is deprotected by treating with TFA to produce Dolutegravir (I).
The Process is as Shown in Scheme-I Below:

The major disadvantage with the above prior-art process is that it involves large no of steps and tedious work-up procedures to isolate the required product. This results a longer period of time cycle is required to produce Dolutegravir (I), which in turn renders the process more costly and less eco friendly. Further the above processes are low yielding and with less purity.
U.S. Pat. No. 8,217,034 discloses variant process for the preparation of Dolutegravir. This process involves the reaction of methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridine carboxylate (XII) with (R)-3-amino-1-butanol (II) to produce (4R,12aS)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[1′,2′,4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (XIII), which further undergoes bromination using NBS to produce (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (XIV). The bromo Compound (XIV) is condensed with 2,4-difluorobenzylamine (IV) in the presence of Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to produce benzyloxy Dolutegravir (XI), which is hydrogenated in the presence of Pd/C to produce Dolutegravir (I).
The Process is as Shown in Scheme-II Below:

The major disadvantage with the above prior art process of preparing Dolutegravir is the use of expensive reagent tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) in coupling step. Use of this reagent on industrial scale is not preferred, which makes the process more expensive.
WO 2011/119566 discloses another variant process for the preparation of Dolutegravir. This process involves the reaction of 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (XV) with acetic acid in presence of methane sulfonic acid to produce 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid (XVI), which is further condensed with (R)-3-amino-1-butanol (II) to produce (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]-oxazine-9-carboxylic acid (XVII). This acid Compound XVII is acylated with 2,4-difluorobenzylamine (IV) in the presence of carbonyldiimidazole (CDI) to produce methoxy Dolutegravir (XVIII), which is demethylated in the presence of lithium bromide (LiBr) to produce Dolutegravir (I).
The Process is as Shown in Scheme-III Below:

The major disadvantage of the above prior art process of preparing Dolutegravir is the use of expensive and highly moisture sensitive reagent, 1,1-carbonyldiimidazole (CDI), during acylation. Use of this reagent on industrial scale is not preferred due to anhydrous conditions required in the process.
(R)-3-Amino-1-butanol (II) is a key precursor used in the preparation of Dolutegravir (I).
Journal of Organic Chemistry 1977, 42(9), 1650-1652 reported a process for the preparation of (R)-3-amino-1-butanol (II) by reacting ethyl crotonate (XIX) with (−)-1-(S)-phenylethylamine (XX) to produce ethyl-3(R)—N-[1(S)-methylbenzyl]amino butyrate (XXI), which is further undergoes reduction with LiAlH4 to produce 3(R)—N-[1(S)-methylbenzyl]aminobutan-1-ol (XXII). Compound (XXII) is further hydrogenating with Pd/C in ethanol to produce (R)-3-amino-1-butanol (II).
The Process is as Shown in Scheme-IV Below:

The major disadvantage of above process is that it involves large number of steps for the manufacture of (R)-3-amino-1-butanol (II). In the chemical synthesis, the number of steps is not advisable for the commercialization of the product. The number of steps is more in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This does not make the suitable chemical process.
U.S. Pat. No. 8,288,575 discloses a process for the preparation of (R)-3-amino-1-butanol (II), wherein methyl (R)-3-aminobutanoate (XXIII) is hydrogenated using ruthenium complex in a solvent.
The Process is as Shown in Scheme-V Below:

The major disadvantage with the above process is that the sensitivity and the use of more expensive catalyst such as ruthenium complex, which is not easier to handle on commercial scale, and this process is not suitable for commercial scale production of (R)-3-amino-1-butanol (II).
US 2011/0275855 A1 discloses a process for the resolution of (R,S)-3-amino-1-butanol (XXV), wherein racemic 3-amino-1-butanol undergoes resolution with (S)-mandelic acid in the presence of an acid different from (S)-mandelic acid to produce (R)-3-amino-1-butanol (S)-mandelic acid salt (IIc), which is further neutralized to produce (R)-3-amino-1-butanol (II).
The Process is as Shown in Scheme-VI Below:

The major disadvantage with the above process is that it involves longer process time, low product yields.
However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
The present invention is related to a process for the preparation of pure Dolutegravir (I), wherein optically active acid addition salt of (R)-3-amino-1-butanol (II) is directly condensed with 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid (XVI) instead of condensing with free base of (R)-3-amino-1-butanol (II).
The present invention is also related to a process for the preparation of pure Dolutegravir (I), wherein, inexpensive and easily handling condensing reagents in the condensation of (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (IV).
The present invention is also relates to a process for the preparation of pure (R)-3-amino-1-butanol (II), wherein 4-hydroxy-2-butanone oxime (XXIV) is subjected to hydrogenation to produce (R,S)-3-amino-1-butanol (XXV), which is further undergoes resolution using D-tartaric acid, followed by de-salting to produce (R)-3-amino-1-butanol (II).